Rethinking the hemorrhagic shock chain of survival: The role, importance, and impact of prehospital blood administration

Hemorrhagic shock is a state of life-threatening circulatory failure resulting from acute blood loss, causing insufficient oxygen delivery to tissues.1 It can occur from traumatic causes and non-traumatic causes, such as gastrointestinal bleeding, obstetric and gynecologic complications, perioperative bleeding, and aneurysmal rupture. In total, hemorrhage is estimated to be responsible for 1.9 million deaths per year worldwide.2 Hemorrhage is the leading cause of preventable death after trauma and is responsible for up to 40% of trauma mortality.3, 4 Hemorrhagic shock is a process that occurs rapidly after major bleeding, and the first minutes to hours are critical to prevent loss of life. Akin to the urgency of sudden cardiac arrest and stroke management, resuscitation systems of care must be in place to provide rapid treatment within this short window of opportunity. Before the introduction of blood products into emergency medical services (EMS), hemorrhagic shock was primarily managed by controlling compressible bleeding, administering tranexamic acid (TXA), transporting rapidly to the hospital, and providing other supportive measures, including airway management and hypothermia prevention. These measures to slow and counteract blood loss have remained essentially unchanged over the past decade. The EMS community has utilized tourniquets since the early 2000s.5, 6 Pelvic binders have been in national guidelines since the early 2010s.7, 8 Junctional tourniquets have gained popularity more recently to address groin, neck, and axillary hemorrhage; however, there is limited strong evidence to support their widespread use.9, 10 Furthermore, these interventions are directed toward compressible hemorrhage, which accounts for a minority of cases of hemorrhagic shock.11 Conversely, in cases of non-compressible bleeding, which make up most hemorrhagic shock cases seen by prehospital clinicians, especially in penetrating, high-energy blunt trauma, and non-traumatic bleeding, prehospital clinicians not equipped with blood products have limited options, outside of TXA, to prevent circulatory collapse. This is supported by evidence that demonstrates hemodynamically unstable patients have worse outcomes when on-scene times are prolonged.12-14 This has led to a strategy of “scooping and running,” emphasizing rapid transport over nearly all other interventions.15 Indeed, expeditious transport of patients to definitive care remains critical. However, despite two decades of emphasis on rapid transport of prehospital trauma patients, outcomes have not substantially improved, and data show that mortality among patients, particularly with noncompressible torso trauma, increases much sooner than the Golden Hour.14, 16 Blood products are the initial resuscitation therapy of choice in the hospital for patients in hemorrhagic shock. Increasingly, blood products are initiated in the prehospital phase of care, closer to the point of injury or illness, enabling EMS to deliver more hemodynamically stable patients to the hospital with improved survival.17 Prompt administration of blood products in the prehospital setting to patients with hemorrhagic shock has been associated with decreased mortality in numerous studies.18-21 It is estimated that thousands more lives could be saved with the addition of prehospital blood products.22-24 As the evidence base for prehospital blood transfusion has grown, it has become increasingly clear that this life-saving intervention should be a component of prehospital care offered nationwide in the United States (U.S.). While the number of EMS agencies carrying blood products has grown significantly, a large majority of systems still do not. We propose that prehospital blood products and field damage-control resuscitation (DCR) be added as a critical link to an updated chain-of-survival framework for patients experiencing hemorrhagic shock. The “Chain of Survival” concept outlines the critical, sequential steps of system-based interventions that need to occur in life-threatening medical conditions. The American Heart Association (AHA) first introduced it as a framework for managing cardiac arrest.25 The concept has been successfully applied to numerous other time-sensitive emergencies, such as stroke, industrial emergencies, drug overdoses, and sepsis.26-31 In general, the chain begins with prevention and mitigation efforts, then progresses toward a prehospital phase, which includes bystander intervention and prehospital EMS care, followed by the in-hospital phase, and then to a recovery period. The existing literature provides a framework for a Chain of Survival focused on hemorrhagic shock (Figure 1).1, 32 We propose adding prehospital blood products and field DCR to the chain, and outline each link in the following sections (Figure 2). The Chain of Survival begins with preventing hemorrhage before it occurs. Many public health efforts have focused on reducing traumatic hemorrhage, including promoting seatbelt and helmet use, discouraging drunk driving, designing safer cars and roads, and preventing firearm and other violent deaths.33, 34 Hospitals have also similarly implemented interventions to decrease death from maternal hemorrhage and perioperative hemorrhage.35, 36 These intervention strategies, implemented before an injury occurs, can significantly reduce mortality and are likely much more effective than secondary and tertiary prevention efforts after injury. For example, it is posited that road safety interventions on speeding, drunk driving, seatbelts, and helmets could prevent between 25% and 40% of all fatal road injuries worldwide, totaling over half a million lives per year.33 Recognition of life-threatening bleeding and immediate hemorrhage control is critical to decrease loss of blood in trauma.16 Life-threatening extremity bleeding should be controlled initially with direct pressure, and if insufficient, a tourniquet should be applied. In the civilian setting, tourniquets have been associated with significantly improved survival and have been shown to be safe when used within the typical transport times in the continental United States.37, 38 Junctional bleeding can be managed with direct pressure and wound packing with either hemostatic or plain gauze. If ineffective for lower-extremity junctional bleeding, junctional tourniquets can be considered, though evidence is limited.9, 10 Immediate compressible hemorrhage control after injury can be performed by anyone adjacent to the point of injury, including laypeople, law enforcement, or EMS personnel. Much like bystander cardiopulmonary resuscitation, the Stop the Bleed campaign emphasizes public access to bleeding control supplies and teaches the public to apply pressure, place tourniquets, and pack wounds for compressible hemorrhage.39 Since its inception, the Stop the Bleed campaign has promoted the placement of bleeding control supplies in recreation areas, schools and universities, hospitals, and large gathering spaces.40-42 Blood products should be administered to all patients in hemorrhagic shock. Blood remains a scarce resource, so it should be used judiciously. Guidelines from the American Association for the Surgery of Trauma and American College of Surgeons Committee on Trauma recommend triggering DCR with systolic blood pressure (SBP) <90 mmHg (or <110 mmHg in those >65 years old), shock index (SBP/HR) >1, lactate >2.5, base deficit >−6, INR >1.5, an unstable pelvis or positive Focused Assessment with Sonography in Trauma (FAST) exam.43 The Prehospital Blood Transfusion Coalition recommends transfusing patients with one or more signs of hypoperfusion (such as altered mental status, pale, cool or clammy skin, delayed capillary refill, tachypnea or EtCO2 <25 mmHg) and SBP <90 mmHg (or <100 mmHg in those over 65 years old) or a weak radial pulse, and a heart rate >100, or a shock index >1.0 in adults or SBP <70 + (age in years/2) and HR >190 for those 1–2 years old or HR >140 for those 2–10 years old.44 Other widely utilized triggers include HR >120 and clinical signs of poor perfusion, such as altered consciousness, cool and clammy skin, or prolonged capillary refill.45 In resource-limited settings, persistent tachycardia and weak or undetectable radial pulses are reasonable triggers for resuscitation. In trauma, a score of two or greater on the Assessments of Blood Consumption (ABC) score, which awards one point each for SBP ≤90, heart rate ≥120, a positive FAST exam, or a penetrating torso injury, can also be used to predict the need for massive transfusion.43 Compared to the ABC score, however, SI ≥1 may be more sensitive for predicting blood product needs.46 Point-of-care diagnostics, such as end-tidal CO2 (EtCO2) monitoring, FAST exams, and prehospital laboratory values, can also aid in diagnosing hemorrhagic shock requiring blood transfusion. In the hands of prehospital clinicians, FAST exams have been shown to have high specificity but low sensitivity in diagnosing hemoperitoneum, similar to what is observed in the emergency department setting.47-49 This additional information in the field may help to guide the appropriate blood product administration and expedite trauma evaluation and surgical intervention. Prehospital lactate measurement has also been shown to be a helpful adjunct to identify patients in hemorrhagic shock. Elevated lactate obtained in the prehospital setting has been associated with the need for in-hospital blood transfusion.50, 51 It has been shown to outperform static vital signs and the shock index in predicting the need for lifesaving interventions. When lactate cannot be directly measured, EtCO2 is strongly inversely correlated with elevated lactate in the setting of trauma.52 The resuscitation of patients in hemorrhagic shock requires more than simply transfusing blood products. It must include focused physiologic targets and adjuncts to prevent coagulopathy, such as TXA, judicious calcium during massive transfusion, and efforts to avoid hypothermia. The concept of DCR, an extension of “Damage Control Surgery” (DCS), emphasizes restoring functional physiology (homeostasis) through early, aggressive hemorrhage control and blood transfusion.53, 54 The concept begins by targeting permissive hypotension with a goal systolic blood pressure of 80–90 mmHg in adults (excluding those with traumatic brain injury) by using a whole blood transfusion strategy. This whole blood strategy can be achieved with either true whole blood, such as Low-Titer O+ Whole Blood (LTOWB), or a 1:1:1 component of RBCs, plasma, and platelets; however, providing 1:1:1 transfusion in the prehospital setting is prohibitively difficult.21, 53 Crystalloids should not be used as a resuscitation fluid as their use is associated with increased mortality and can result in dilutional coagulopathy and hypothermia.53, 55 Tranexamic acid is an adjunct to prevent fibrinolysis and has been associated with reduced mortality in trauma and post-partum hemorrhage. A systematic review and meta-analysis incorporating data from seven RCTs comparing TXA with placebo demonstrated reduced 24-hour and one-month mortality, as well as no increased risk of vascular occlusive events.56 Tranexamic acid should be administered as soon as possible, ideally within one hour after an injury. Infusion greater than three hours after injury is associated with increased mortality. In post-partum hemorrhage, a 2018 Cochrane review also demonstrated reduced mortality from TXA use with no increased risk of thromboembolic events.57 If multiple units of blood product are transfused, calcium can be administered to prevent citrate-induced hypocalcemia and coagulopathy.44 Hypocalcemia is strongly associated with mortality, though it is unclear if there is an actual causal effect or if it is a physiological marker of severe derangement.58 Some guidelines recommend administering calcium, either 10 mL of 10% calcium chloride or 30 mL of 10% calcium gluconate, after the first unit of blood and every four subsequent units, or after the second unit of blood.43, 44, 53 It is important to note that there is no data associating improved outcomes with calcium administration. Particularly in volume-depleted patients, clinicians should exercise caution to avoid causing hypercalcemia. Growing evidence supports that prehospital blood products are lifesaving in hemorrhagic shock. The modern era of prehospital blood transfusion started during the armed conflicts in Iraq and Afghanistan, when the use of blood products in hospitalized trauma patients was linked to better survival rates.59 Evidence for prehospital blood products followed shortly after and has primarily been in the trauma population. The blood products most commonly available to civilian EMS services in the U.S. are whole blood (often Low Titer O-Positive), red blood cells (RBC), and liquid plasma. Red blood cells were the main oxygen-carrying blood product available until the broader expansion of LTOWB in recent years. Transfusion with plasma alone has been evaluated in two major randomized controlled trials, the PAMPer trial and the COMBAT trial. The landmark multi-center PAMPer trial compared thawed plasma with crystalloid in patients transported via air ambulance to a trauma center and demonstrated decreased 24-hour and 30-day mortality, as well as a lower prothrombin time ratio in the plasma group.18 The smaller single-center COMBAT trial compared thawed plasma with crystalloid, was initiated by ground ambulances, and did not demonstrate a mortality benefit at 28 days, stopping for futility before complete enrollment.60 The major randomized controlled trial evaluating RBC transfusion is the RePHILL trial, which compared RBCs plus lyophilized plasma to sodium chloride.61 This study demonstrated no difference in the primary composite outcome of survival to discharge or lactate clearance, nor survival alone, but was limited by incomplete enrollment. A secondary analysis of the PAMPer trial demonstrated that RBC transfusion alone or RBC plus plasma, compared to crystalloid, was associated with decreased 30-day mortality, and the RBC plus plasma cohort had the highest survival benefit.19 When combined with calcium and TXA, this prehospital “Advanced Resuscitative Care” bundle has been associated with improved survival.62 Retrospective studies analyzing prehospital RBC transfusions alone have demonstrated similar survival rates at hospital arrival and at 30 days.63-65 Whole blood has become a popular choice for resuscitation in trauma centers because observational studies show improved mortality and reduced use of total blood products compared to component therapies.66, 67 In the prehospital setting, observational research has yielded similar results with whole blood administration, demonstrating improved survival rates in patients with hemorrhagic shock.68-70 So far, there have been no published randomized controlled trials (RCTs) comparing whole blood to component therapy in the prehospital setting; however, the Type O Whole Blood and assessment of age during prehospital Resuscitation (TOWAR) trial has completed enrollment, while the Trauma resuscitation with Low-Titer Group O Whole Blood Or Products (TROOP) and the Study of Whole Blood in Frontline Trauma (SWiFT) trials are currently underway.71-73 Despite the importance of prehospital blood administration, rapid transport to an appropriate receiving center remains a critical component in the chain of survival. Blood should be administered expeditiously, ideally while patients are actively transported. Numerous studies have supported that rapid transport of unstable trauma patients is associated with improved mortality.12-14 Some research has even demonstrated that transport by private vehicle or police is associated with decreased mortality.15, 74, 75 These studies, however, do not clearly stratify for blood product administration by EMS clinicians. A post-hoc analysis of 626 patients from the PAMPer and COMBAT trials showed that plasma transfusion, compared to standard care, in those with prolonged transport times (>20 min) was associated with a significant decrease in 28-day mortality.76 Recent research has demonstrated that a prehospital “Advanced Resuscitative Care” bundle for traumatic hemorrhage that includes blood products may increase total prehospital time, but deliver the first unit of blood to the patient much faster than if it were delayed to the hospital.77 Despite the delay in arrival at the hospital, this bundle was associated with a significant decrease in in-hospital mortality. Upon arrival at the receiving center, the chain continues with ongoing DCR, following the same principles as those initiated in the field. In the hospital, patients continue to receive blood products, TXA, and calcium when appropriate. In patients who have not yet received blood products, this is their first opportunity for transfusion. In some cases, patients whom EMS has adequately resuscitated may not need as much resuscitation at the hospital. At most centers, blood will be transitioned to 1:1:1 component transfusion when massive transfusion is expected. When possible, rapid definitive hemostasis should be achieved via surgical and/or endovascular approaches.78 In trauma, operative intervention should follow DCS practices, prioritizing control of hemorrhage and contamination during the index surgery, while delaying all other definitive interventions for future surgeries.53 This practice prevents the significant physiological stress caused by lengthy surgeries and spreads these procedures over several days, allowing for proper resuscitation between each trip to the operating room. After initial resuscitation and hemorrhage control, care in the intensive care unit focuses on monitoring for organ failure and preventing secondary injury.1 Blood transfusion can be transitioned from ratio-driven to goal-driven cross-matched products, and coagulopathy correction can be guided by thromboelastography or rotational thromboelastometry.79 Metabolic and electrolyte derangements can be corrected, and normothermia can be restored. And, complications of massive transfusion, such as abdominal compartment syndrome and respiratory failure, can be addressed. As clinical improvement occurs, physical and occupational rehabilitation can help patients regain functional abilities. Long-term, many patients require outpatient rehabilitation and ongoing mental health support.80 In a high-functioning system, the chain culminates in feedback that leads to improvements in all previous aspects of care. 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